Nivolumab-induced lichen planus

Introduction

Renal cell carcinomas (RCCs) account for 90% of all malignant neoplasms of the kidney, with an estimated 73,820 newly diagnosed cases of kidney tumors (44,120 men and 29,700 women) and 14,770 deaths (9820 men and 4950 women) in 2019. ¹ The most common types of renal cancer in adults are clear cell (75% of cases) and papillary (10% of cases) RCC, and rarer types include chromophobe (≤5% of cases), collecting-duct and renal medullary (each in ≤ 1% of cases), and translocation (<1% of cases) carcinoma. ² Sporadic cases of papillary (or clear cell) renal carcinomas containing chromosomal translocations involving the TFE3 gene at chromosome Xp11.2 are rare, more usually occurring in children and young adults. ³

Until 2006, immunotherapy had represented the main treatment for patients with advanced renal cancer. The most widely studied agents were IFN-alpha and aldesleukin (human recombinant interleukin-2 (IL-2)). IFN-alpha demonstrated low but reproducible response rates of 10 to 20% with particular durable responses. Toxicity associated with high-dose bolus IL-2 is related to increased vascular permeability and often necessitates treating patients in an intensive care setting. IL-2 has been associated with a 4% incidence of treatment-related death. ⁴ In patients with cytokine-refractory disease, sunitinib, which is an oral broad-spectrum receptor tyrosine kinase inhibitor, demonstrated a response rate of 41% and a progression-free survival (PFS) of 8.2 months, which led to approval for second-line therapy in 2006. ⁵ A randomized phase III trial that compared sunitinib with IFN in previously untreated patients with clear cell carcinoma demonstrated superior overall response rate, PFS, and overall survival (OS) in the sunitinib arm. ⁶ Nowadays, promising data have emerged using anti-PD-1 and anti-PD-L1 therapies in advanced kidney cancer. Nivolumab (a fully human immunoglobulin G4 PD-1 checkpoint inhibitor antibody) has received Food and Drug Administration (FDA) approval for the treatment of advanced RCC in patients who have received prior antiangiogenic therapy based on the results of a randomized, open-label, phase III study that compared nivolumab with everolimus in previously treated patients with RCC and demonstrated a significant OS benefit for nivolumab. ⁷

The foremost side effects of anti-PD-1 therapy are immune related and include rash, pruritus, vitiligo, thyroiditis, diarrhea, hepatitis, diabetes mellitus, hypophysitis, and pneumonitis. ⁸ Lichenoid reactions with immune checkpoint inhibitors (ICIs) have been reported. ⁹ We report a patient who presented with lichen planus after receiving nivolumab for advanced RCC.

Case presentation

In May 2016, a 25-year-old woman, with no history of any disease, underwent left simple nephrectomy and retroperitoneal lymph node dissection for stage IV metastatic RCC (metastases to cervical, mediastinal, and intrabdominal lymph nodes). Pathological examination indicated tubular and tubulovillous translocation carcinoma, which is a very rare subtype of RCC. She received first-line IFN-alpha subcutaneously for two months and disease has progressed. In August 2016, she developed new metastatic lymph nodes and the disease had progressed. She was treated with sunitinib 50 mg/day, four weeks on and two weeks off for two years as second line treatment. Hypothyroidism and pretibial edema were observed as sunitinib side effects. After the second progression of the disease, nivolumab 240 mg, every two weeks, was introduced in September 2018. In the fifth month of treatment, the patient was admitted to the hospital with eruptions along the anterior region of her left leg, associated with severe itch. Physical examination showed multiple purple papules, sometimes coalescing into plaques characterized by whitish streaks and concomitant presence of tense bullous lesions on her left leg (Figure 1 and 2). She was consulted to the dermatologist and a diagnosis of lichen planus was made. The lesions were treated with clobetasol propionate cream and topical methylprednisolone twice daily for four weeks, and with this treatment, the lesions regressed. Since there was a partial regression for the metastatic RCC with nivolumab, it was decided to continue nivolumab treatment. The lichenoid skin lesions did not reoccur in the subsequent treatment periods, and her disease partially regressed with nivolumab.

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Figure 1.

Purple papules and plaques in the dorsum of the left foot.

Discussion

We report a nivolumab-induced lichen planus as an immune-related adverse event in a young woman that was treated for advanced RCC. After the ninth dose of nivolumab treatment, she was consulted to dermatology because of skin lesions, and lichen planus was diagnosed.

ICIs are medications that activate anti-tumor responses by disrupting the inhibitory signaling to T cells. Nivolumab is an ICI that selectively blocks the PD-1 receptors found on the T cells. Nivolumab has been approved by the FDA for the treatment of multiple cancers such as RCC, lung cancer, melanoma, Hodgkin’s lymphoma, squamous cell cancer of head and neck, urothelial carcinoma, colorectal carcinoma, and hepatocellular carcinoma.

Skin reactions are the most common side-effects under treatment with anti-PD-1 or anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and play an important role for patients and usually develop early in the course of treatment. However, serious skin toxicities are rare and do not usually require dose reductions or treatment discontinuation. Patients had skin reactions like rash and pruritus in 28–37% and vitiligo in 9–11% under anti-PD-1 therapy (nivolumab and pembrolizumab). ⁹ Furthermore, rare cutaneous side-effects like psoriasis vulgaris, exfoliative dermatitis, and erythema multiforme have been documented.

Biolo et al. reported a metastatic RCC case that presented with linear bullous lichen planus was associated with nivolumab therapy. ¹⁰ Systemic corticosteroid was used because the lesions of their patient did not regress with topical interventions. Since the lesions of our case responded very well to topical treatment, there was no need for systemic treatment.

Maarouf et al. reported a lichen planus reactivation in a patient with a strong personal and family history of the disease that was treated with nivolumab for stage 4 non-small cell lung cancer. ¹¹ In contrast to this case, our patient did not have a history of personal or family dermatological disease. As in the case presented by Maarouf et al., our case responded very well to topical treatments, and there was no need to interrupt nivolumab therapy.

We also assessed causality between nivolumab and lichen planus using the Naranjo adverse drug reaction probability scale. ¹² We obtained a score of 5 for nivolumab with a probable adverse drug reaction score of 5 to 8.

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Figure 2.

Maculopapular lesions on the lateral aspect of the left foot.